The generation of an effective AIDS vaccine is complicated by our incomplete knowledge of the correlates of immune protection during HIV infection. As such, it has been difficult to compare the potential clinical efficacy of the vectors that are currently considered as candidate AIDS vaccines. Notwithstanding these conceptual limitations, a number of clinical and pre-clinical immunogenicity indicate that replication-defective adenovirus (Ad) vectors based on the human serotype 5 (AdHuS) can induce strong and persistent immune responses to HIV/SIV antigens. Unfortunately, pre-existing exposure and/or immunity to human Ads, and particularly to AdHuS, may hamper the efficacy of AdHu5-based AIDS vaccines. The overarching hypothesis of this proposal is that chimpanzee (chimp) Ad-based vectors represent promising candidate AIDS vaccines as they show a profile of immunogenicity that is as good, if not better, than that observed for AdHuS while presenting only minor problems in terms of pre-existing immunity. The use of AdC6 and AdC7 as vaccine vectors was pioneered in the laboratory of Dr. Ertl, P.I. of this IPCAVD application. In Project #3 we propose to study in detail the impact of pre-existing Ad-specific T cells upon chimp Ad vaccine induced immune responses. In the first Aim, we will determine the prevalence, magnitude, functionality, and phenotype of naturally occurring AdC6 and AdC7-specific T cells in humans from North America and Africa. In Aim 2 we will determine whether pre-existing AdHuS-specific T cells affect the immunogenicity of AdC6 and AdC7 SIV vaccine vectors, and alter the protective capacity of vaccine-induced cells after SIV challenge in rhesus macaques. In the final Aim, we will examine these same issues in humans vaccinated with the AdC6 and AdC7 vectors in phase I safety trials and a phase IIA immunogenicity trial. The levels of pre-existing AdHuS, AdC6, and AdC7-specific T cells will be assessed prior to challenge, and their impact upon vaccine immunogenicity and quality will be determined. Ultimately, the proposed studies are aimed at defining the impact of pre-existing Ad-specific T cell responses upon the efficacy of chmp Ad-based AIDS vaccines in inducing host responses that can contain virus replication, prolong disease-free survival, and decrease secondary transmission. Definition of the characteristics of such effective immune responses will also advance our understanding of the correlates of immune protection to be pursued in future efforts of AIDS vaccine development.